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Page 4 of 18 Stuivenberg et al. Microbiome Res Rep 2025;4:11 https://dx.doi.org/10.20517/mrr.2024.22

Figure 1. Distribution of the study participants among the clinic population of 3,056 patients in the linear regression model. Measured
TPA is plotted against the standardized predicted value of plaque area based on the risk factors in the regression model: age, sex,
diabetes, smoking status, serum creatinine, systolic and diastolic blood pressures, total cholesterol, triglycerides, LDL-C, and HDL-C.
Control patients are shown as grey dots. The red dots represent study participants with residual scores > 2, i.e., they are the 5%
extreme cases with unexplained atherosclerosis, with more plaque than predicted by risk factors by 2 standard deviations or more.
Green dots represent protected patients; these are the 5% extremes with much less plaque than predicted, with residual scores < -2;
orange dots represent patients with explained atherosclerosis, whose plaque burden is predicted by the risk factors, with residual
[1]
scores between -2 and 2. Reproduced by permission of Elsevier from . TPA: Total plaque area; LDL-C: low-density lipoprotein-C; HDL-
C: high-density lipoprotein-cholesterol.

[21]
elevated risk of developing atherosclerosis in patients with impaired renal function .

Indeed, dietary and pharmacological treatments to lower TMAO have been developed; for instance,
switching from red meat to white meat or vegetarian/vegan meals significantly reduced plasma TMAO over
one month . Additionally, two inhibitors are currently under development: one targets choline
[22]
trimethylamine lyase , a bacterial enzyme involved in generating trimethylamine from nutrients such as
[23]
phosphatidylcholine and carnitine, while the other inhibits flavin-containing monooxygenase 3 , a hepatic
[24]
enzyme that converts trimethylamine into TMAO. Given the microbial origins of the metabolite, the
potential for probiotics to reduce plasma TMAO is also a subject of inquiry.

It is well established that the gut microbiota composition of atherosclerosis patients drastically differs from
that of healthy controls. Typically, these patients present an increased abundance of Enterobacteriaceae and
Streptococcus species . However, additional studies have also linked subclinical markers of atherosclerosis
[3]
[25]
to increased levels of Collinsella, where the healthy controls had more Roseburia and Eubacterium . In
addition, bacterial nucleic acids originating from the genera Chryseomonas, Veillonella, and Streptococcus
were detected in atherosclerosis plaques, with several of these phylotypes also being identified in the
gut [25,26] . Furthermore, a metagenome-wide association study revealed that atherosclerosis patients differ
from healthy controls not only in gut microbiome composition, but also in its functional and metabolic
capacity . This is particularly true for the metabolism and transport of molecules crucial for cardiovascular
[3]